CN1651454A - Preparation method of steroid medicine for treating respiration channel disease and its intermediate - Google Patents
Preparation method of steroid medicine for treating respiration channel disease and its intermediate Download PDFInfo
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- CN1651454A CN1651454A CN200410086732.3A CN200410086732A CN1651454A CN 1651454 A CN1651454 A CN 1651454A CN 200410086732 A CN200410086732 A CN 200410086732A CN 1651454 A CN1651454 A CN 1651454A
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- tertiary butyl
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- 238000002360 preparation method Methods 0.000 title claims description 13
- 239000003814 drug Substances 0.000 title abstract description 6
- 150000003431 steroids Chemical class 0.000 title abstract description 5
- 201000010099 disease Diseases 0.000 title abstract 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract 2
- 230000029058 respiratory gaseous exchange Effects 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 30
- 230000002378 acidificating effect Effects 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 82
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- -1 isobutyl- Chemical group 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 230000007062 hydrolysis Effects 0.000 claims description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 9
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 8
- 238000007127 saponification reaction Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 6
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 claims description 6
- 239000011707 mineral Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 150000002460 imidazoles Chemical class 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 3
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 150000005826 halohydrocarbons Chemical group 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 238000006884 silylation reaction Methods 0.000 claims description 2
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims 1
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 210000002345 respiratory system Anatomy 0.000 abstract 1
- 239000002585 base Substances 0.000 description 39
- 238000003756 stirring Methods 0.000 description 22
- 150000003527 tetrahydropyrans Chemical class 0.000 description 20
- 238000001953 recrystallisation Methods 0.000 description 17
- 229910052710 silicon Inorganic materials 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 229910052760 oxygen Inorganic materials 0.000 description 13
- 239000001301 oxygen Substances 0.000 description 13
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 12
- 239000010703 silicon Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 239000003921 oil Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 230000002194 synthesizing effect Effects 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000005046 Chlorosilane Substances 0.000 description 3
- 208000018569 Respiratory Tract disease Diseases 0.000 description 3
- 125000005466 alkylenyl group Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 229920005654 Sephadex Polymers 0.000 description 2
- 239000012507 Sephadex™ Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- JSZOAYXJRCEYSX-UHFFFAOYSA-N 1-nitropropane Chemical compound CCC[N+]([O-])=O JSZOAYXJRCEYSX-UHFFFAOYSA-N 0.000 description 1
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- AKQOBHZKBDHWQI-BZEFIUHZSA-N O[C@H]1C[C@@H](CCC1)N1C(C2(C3=C1N=C(N=C3)NC1=CC=C(C=C1)S(=O)(=O)NC([2H])([2H])[2H])CC2)=O Chemical compound O[C@H]1C[C@@H](CCC1)N1C(C2(C3=C1N=C(N=C3)NC1=CC=C(C=C1)S(=O)(=O)NC([2H])([2H])[2H])CC2)=O AKQOBHZKBDHWQI-BZEFIUHZSA-N 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229940127108 compound 5g Drugs 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
A steroid medicine for treating the diseases in respiratory tract is prepared through the reaction between an intermediate and cyclohexyl formaldehyde under the action of acidic catalyst. Its intermediate and its preparing process are also disclosed.
Description
Technical field
The present invention relates to a kind of Preparation Method And Their Intermediate for the treatment of the steroid drugs of respiratory tract disease.
Background technology
Following structural formula (I) compound (CAS:126544-47-6) be a kind of treat respiratory tract disease especially asthma steroid drugs, curative effect [Drugs 2004:64 (5): 511-519] is preferably arranged, successively ratified listing in 2004 in Australia, Britain.
Hispanic Jose Calatayud discloses the method for a kind of preparation formula (I) compound in United States Patent (USP) (patent No. US5482934, open day is orders June 9 in 1996):
Isobutyric anhydride acidylate in pyridine of 16 alpha-hydroxy prednisonlones [hereinafter to be referred as four hydroxyl things (formula VI)] and 5eq gets three isobutyryl ester things (formula VII).Three acyl group things (formula VII) carry out what is called " hydrolysis-acetalation " reaction with hexahydrobenzaldehyde subsequently under acidic conditions, 16,17 ester group is slow hydrolysis and horse back and hexahydrobenzaldehyde condensation formation acetal under acidic conditions, but the ester of 21-position can not be hydrolyzed.The gained acetal is 22 R configuration and a S configuration epimer (VIII).Its generation ratio is difference by the difference of selected solvent, particularly selected an acidic catalyst.For example, in dry HCl, as use the PTS/ dioxane, then can get 85～90% S configuration.Pure R configuration or S configuration can be used Sephadex (sephadex) LH-20 or LH-60 usefulness heptane/ethanol or the capable column chromatography of ethanol/water wash-out and get.This patent adopts ethanol/acetone/water three-phase solvent recrystallization, can get 22 S configuration bodies of 99.99% purity.How this of Calatayud piece patent mainly lays particular emphasis on 2 S configuration bodies of Synthetic 2, its pharmacology result is that the biological activity of 22 S configurations is better than 22 R configurations, in fact, formula (I) compound is the same with budesonide, and the activity of 22 R configuration bodies is still greater than 22 S configurations.
Thereafter, the Gutterer of German BYK Gulden company has applied for that a kind of preparation is configured as main formula (I) compound patented method (patent No. is US5733901, and open day is on March 31st, 1998) with 22 R:
Four hydroxyl things (formula VI) earlier with the hexamethylene formaldehyde condensation and the 22-hexamethylene formaldehyde thing (formula IX) that contracts, it is 22 R configurations of blended: S configuration epimer.And then the isobutyl esterification and formula (I) compound (I).Wherein, the ratio of 22 R/S in the acetal one step products therefrom (formula IX) according to reaction conditions for example solvent for use, acid catalyst kind and feed ratio, alters a great deal.With HClO
4Be catalyzer, Nitromethane 99Min. is a solvent, and products therefrom (formula IX) R/S reaches 92/8.
Gutterer discloses the method for another preparation formula (I) compound in United States Patent (USP) (US5728826, open day is on March 17th, 1998):
The silicon etherificate of 21-position hydroxyl can adopt classical literature method (chlorosilane and imidazoles are in DMF) to carry out.Chlorosilane can be the chloro trimethyl silane, chloro dimethyl t-butylsilane or chloro dimethyl 1,1, and 2-trimethylammonium propyl silanes etc., silicon etherificate yield are generally＞90%.Then, silicon ether thing (formula XI) is carried out recrystallization, just can improve the ratio of 22 R configurations with all kinds of SOLVENTS.When the silicon ether is a dimethyl, 1,1, during 2-trimethylammonium propyl group, best with the re-crystallizing in ethyl acetate effect, 22 structure R type optical body content can reach more than 98%, and the recrystallization yield is about 80%.At last, use acid (HOAc, HCl or CF again
3COOH) hydrolysis silicon ether becomes acetal thing (formula XI).
Gutterer discloses in another part patent (patent international publication number WO98/09982, March 12 1998 international publication day), and after 21 direct isobutyryls of hydroxyl of acetal thing changed into formula (I) compound, recrystallization improved 22 R configuration content to 98% again.Adopt the organic solvent recrystallization that some can be miscible with water, organic solvent preferred alcohol, methyl alcohol, Virahol and acetone in example.
Gutterer discloses ketal conversion method synthesis type (I) compound in patent (patent international publication number WO 02/38584, May 16 2002 international publication day):
R wherein
5Be H, perhaps isobutyryl; R
6, R
7Be C
1-4Alkyl is preferably methyl.
Summary of the invention
The method that the purpose of this invention is to provide a kind of new preparation formula (I) compound compound.
The purpose of this invention is to provide a kind of new intermediate.
Another object of the present invention provides a kind of preparation method of new intermediate
The compound of formula (I), chemical name: 16 α, 17 α [(R)-cyclohexyl methyne dioxygen base]-11 beta-hydroxies-21-(isobutyl acyloxy) pregnant steroid-1,4-diene-3, the 20-diketone, its 22 is R configuration (CAS:126544-47-6).
Contain the synthetic method of chiral centre compound for all suc as formula (I) compound etc., should consider synthetic step and yield, the prior ratio that also should consider its epimer, because the pharmacological action of different epimers often is different, and some epimer may produce toxic side effect.Pharmacological tests shows that the biological activity of 22R formula (I) compound is wanted several times and is better than its 22S epimer [Michael Stoeck etc., J, Pharmac ﹠amp; Exp.Ther.309:249-258,2004].The inventor is surprisingly found out that in a large amount of deep researchs are explored, and uses suitable midbody compound in appropriate solvent, under appropriate reaction conditions, can obtain formula (I) compound, and yield is up to 89%, and 22 R configuration content reach 88%.
New midbody compound provided by the invention is the compound of following general formula (II),
R wherein
1Be selected from hydrogen, tetrahydropyrans (THP) base or structure substituting group as shown in the formula (A):
Wherein, R
2, R
3And R
4Can be identical or different, be selected from C independently of one another
1～C
7Alkyl or phenyl; R
2Preferably from methyl, isobutyl-, the tertiary butyl, 1,1,2-trimethylammonium propyl group (thexyl), phenyl; R
3Preferably from methyl, isobutyl-, the tertiary butyl, 1,1,2-trimethylammonium propyl group, phenyl; R
4Preferably from methyl, isobutyl-, the tertiary butyl, 1,1,2-trimethylammonium propyl group, phenyl.R
2Be preferably methyl especially; R
3Be preferably methyl especially; R
4Preferred tertiary butyl especially, 1,1,2-trimethylammonium propyl group.
Above-mentioned midbody compound (formula II) is the intermediate as synthesis type (I) compound.
The method of a kind of preparation formula provided by the invention (I) compound, it comprises that described general formula (II) compound in the presence of an acidic catalyst, reacts with hexahydrobenzaldehyde.
The reaction conditions of described reaction can be the conventional or known condition in this area.Described reaction can be carried out in the solvent that be fit to adopt, and it can be selected from ether, and for example 1,4-oxygen six rings, isopropyl ether and tetrahydrofuran (THF); Ketone is as acetone; Ester is as ethyl acetate; Halohydrocarbon, as methylene dichloride, chloroform; Nitroparaffins are as Nitromethane 99Min.; Also can be not with an organic solvent.Organic solvent is preferred 1,4-dioxane, tetrahydrofuran (THF), methylene dichloride, chloroform, acetone, Nitromethane 99Min. or isopropyl ether.
Described an acidic catalyst can be the conventional or known an acidic catalyst in this area, can be selected from sulfonic acid, as methylsulfonic acid, tosic acid; Mineral acid, example hydrochloric acid, Hydrogen bromide, perchloric acid, Tetrafluoroboric acid and hydrofluoric acid.Under with an organic solvent situation not, also increase the amount of an acidic catalyst, be used as solvent.Described catalyzer can be methylsulfonic acid, perchloric acid, tosic acid, Tetrafluoroboric acid, hydrofluoric acid.
Described reaction can be carried out under-30 ℃～60 ℃ temperature of reaction, and preferred-20 ℃～40 ℃, more preferably-15 ℃～10 ℃.
In described reaction, work as R
1For hydrogen, tetrahydropyrans (THP) base or-Si (R
2) (R
3) R
4The time, described general formula (II) compound with the hexahydrobenzaldehyde reaction, obtains formula (I) compound in the presence of an acidic catalyst.Described general formula (II) compound, catalyzer and hexahydrobenzaldehyde can almost be present in the reactor simultaneously, react.Also can be earlier described general formula (II) compound be reacted for some time in an acidic catalyst earlier, for example 10～20 minutes, treat on 16 the THP base or-Si (R
2) (R
3) R
4After hydrolysis is fallen, add the hexahydrobenzaldehyde reaction again.
Described reaction is carried out appropriate postprocessing after can carrying out 1～12 hour, and described reaction products therefrom formula (I) compound can be according to the conventional or known method separation in this area, purifying.For example with reference to the method for patent international publication number WO98/09982.
The inventor finds, in the reaction of preparation formula of the present invention (I) compound, works as R
1During for THP base or silylation, the THP base on 16 of the formula II compounds or-Si (R
2) (R
3) R
4Can be fallen by an acidic catalyst hydrolysis, and react with hexahydrobenzaldehyde simultaneously, obtain formula (I) compound, yield can reach 84%, and R configuration content is 70%.Thereafter, the inventor also finds, if earlier formula II compound (is worked as R
1For THP base or-Si (R
2) (R
3) R
4The time) in an acidic catalyst, reacted 10～20 minutes earlier, treat 16 the THP base or-Si (R
2) (R
3) R
4After hydrolysis is fallen, add the hexahydrobenzaldehyde reaction again, then the R configuration content of gained formula (I) compound can be brought up to more than 86%, and yield also can reach about 89%.If with 11 β, 16 α, 17 α, 21-tetrahydroxy-pregnant steroid-1,4-diene-3,20-diketone-21-isobutyrate is a raw material, the R configuration content of the formula of its gained (I) compound can be brought up to more than 89%.
The invention provides a kind of method of preparation described general formula (II) compound, it comprises
(1) with 11 β, 16 α, 17 α, 21-tetrahydroxy-pregnant steroid-1,4-diene-3,20-diketone-21-acetic ester (being the compound of Formula Il I) is a raw material,
Under acidic conditions, react with dihydropyrane (DHP); Or under alkaline condition, with the reaction of following formula (B) compound,
R wherein
2, R
3, R
4Can be identical or different, represent C independently of one another
1-C
7Alkyl or phenyl, X are a suitable leavings group, react following formula (IV) compound:
R wherein
1Be the THP base, or-Si (R
2) (R
3) R
4
(2) (1) step gained formula (IV) compound saponification get the formula V compound,
Wherein, R
1Be the THP base, or-Si (R
2) (R
3) R
4
(3) with (2) step gained formula V compound isobutyric anhydride, to its 21-position hydroxyl isobutyl acidylate;
Promptly get product R
1For THP base or-Si (R
2) (R
3) R
4Substituent general formula (II) compound;
With gained isobutyl acidylate selectivity of product ground its THP base of acidic hydrolysis or 16-Si (R
2) (R
3) R
4, promptly get R
1General formula (II) compound for hydrogen.
In (1) step, described acidic conditions comprises tosic acid (PTS), HClO
4Deng; Perhaps, described alkaline condition can be provided by organic bases.Described organic bases can be one or more in this area routine or the known organic bases, preferred triethylamine, DIEA, N-methylmorpholine, piperidines, imidazoles, pyridine or piperazine.Described reaction can be carried out in aprotic organic solvent.Described aprotic organic solvent can be the conventional or known aprotic organic solvent in this area, preferred methylene dichloride, dimethyl formamide or tetrahydrofuran (THF).
R in formula described in (1) step (B) compound
2, R
3, R
4Can be identical or different, represent C independently of one another
1-C
7Alkyl or phenyl, R
2Preferably from methyl, isobutyl-, the tertiary butyl, 1,1,2-trimethylammonium propyl group, phenyl; R
3Preferably from methyl, isobutyl-, the tertiary butyl, 1,1,2-trimethylammonium propyl group (thexyl), phenyl; R
4Preferably from methyl, isobutyl-, the tertiary butyl, 1,1,2-trimethylammonium propyl group, phenyl.R
2Be preferably methyl especially; R
3Be preferably methyl especially; R
4Preferred tertiary butyl especially, 1,1,2-trimethylammonium propyl group.
At leavings group described in (1) step, can be selected from chlorine, bromine or iodine.Described formula (B) compound is preferably chloro dimethyl t-butylsilane.Described reaction can at room temperature be carried out 0.5～10 hour.
In (1) step, react or the silicon etherificate with DHP fully at 16 α hydroxyls of formula described in the described reaction (III) compound, and 11 β hydroxyls and 17 hydroxyls since steric hindrance greatly and not with DHP reaction or by the silicon etherificate, so the formula IV compound crude product yield of gained is almost quantitative.
In (2) step, described saponification can be carried out under this area routine or known condition.Described saponification is in organic alcoholic solution of mineral alkali, at room temperature carries out, and here, mineral alkali is selected from sodium hydroxide, potassium hydroxide, and organic alcohol is selected from methyl alcohol, ethanol, propyl alcohol or Virahol, handles 0.5h under the room temperature.Work as R
1During for the dimethyl t-butylsilane
1H-NMR shows 0.01,0.06, and the 0.86ppm place can see two the methyl peaks and the tertiary butyl peak of silicon ether respectively; Work as R
1During for the THP base
1H-NMR shows 4.20, and the 3.60ppm place can see the THP base respectively
With
The peak.After the saponification of formula (IV) compound, 21-position acetoxyl optionally is hydrolyzed into compound (formula V),
1H-NMR shows that the methyl peak of the ethanoyl at 2.17ppm place disappears;
In (3) step, described isopropylformic acid anhydridization can carry out under this area routine or known condition.Preferably at K
2CO
3In/the acetone soln, to its 21-position hydroxyl isobutyl acidylate.The products therefrom separation and purification promptly gets pure R
1For the THP substituting group or-Si (R
2) (R
3) R
4General formula (II) compound, H-NMR shows, 1.20 and the 1.16ppm place two methyl peaks of isobutyryl appear.Products therefrom also can separate, acidolysis immediately, preferred 2N HCl, optionally the THP base in its 16 of the hydrolysis or-Si (R
2) (R
3) R
4, obtain R
1Be i.e. 11 β of general formula (II) compound of hydrogen, 16 α, 17 α, 21-tetrahydroxy-pregnant steroid-1,4-diene-3,20-diketone-21-isobutyrate.
The advantage of method provided by the invention is, we can be from steroidal industry tetrahydroxy thing-21-acetic ester (formula III) commonly used, by with DHP reaction or silicon etherificate, saponification, isobutyl acidylates etc. promptly get tetrahydroxy-21-isobutyrate (formula II).The existence of this 21-isobutyrate side chain makes 16, and the hydroxyl of 17-position and hexahydrobenzaldehyde are achieved asymmetric acetalation, the production of high yield (I) compound, and wherein 22R content reaches 88%.
On the surface, this patent four-step reaction synthesis type (I) compound.Yet in fact, the acetic ester that saponification is 21 becomes four hydroxyl things (formula VI), and 21 isobutyl acidylate, is that any synthetic route of preparation formula (I) compound is necessary; And desiliconization ether or one step of THP protecting group, as embodiments of the invention 5 or 8; And the method for embodiment 12 or 14 (seeing below), also can save.In fact, DHP reaction that method of the present invention is only many or one step of silicon etherificate, but DHP or chlorosilane cheapness, and also should the step yield almost quantitative.The significance of route of the present invention is that it is different from various countries' patented method synthetic to formula (I) compound, is a method that formula (I) compound of the synthetic high 22R content of originality is arranged.
Embodiment
Below will the invention will be further described by embodiment, these descriptions are not that content of the present invention is done further to limit.One skilled in the art will understand that to be equal to replacement to what technical characterictic of the present invention was done, or corresponding the improvement, still belong within protection scope of the present invention.
Embodiment 1 16 α-(tertiary butyl dimethyl Si base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-
Diene-3,20-diketone-21-acetic ester synthetic
With 1g (2.4mM) 11 β, 16 α, 17 α, 21-tetrahydroxy-pregnant steroid-1,4-diene-3, the t butyldimethylsilyl chloride alkane of 20-diketone-21-acetic ester and 1.59g (10.5mM), 1.21g imidazoles (17.8mM) reacts under the room temperature in 10ml DMF and spends the night, and shows until TLC to react completely.The 10%HCl solution termination reaction that adds 10ml.With 10ml ethyl acetate extraction three times, merge organic layer, again with twice of 10%HCl washing organic layer; Use 3%NaHCO
3Wash three times, use the 10ml water washing more once.Use Na
2SO
4Drying concentrates, with acetone/sherwood oil recrystallization, and the crystallization after-filtration, promptly get 16 α-(tertiary butyl dimethyl Si base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3, the little yellow crystal 1.13g of 20-diketone-21-acetic ester, yield 89%, m.p.:155.5～158.5 ℃.Ultimate analysis: C
29H
44O
7Si, calculated value: C 65.41%, H 8.27%; Measured value: C 65.28%, H 8.16%.IR(KBr，cm-1)：3423(υOH)，1758，1732(υc＝o)，1655(υc＝o)，1614(υc＝c)，1171-1149(υc-o-c)。
1H-NMR(300MHz，CDCl
3)：δ，ppm，0.01，0.06(2×3H，S，Si(CH
3)
2)，0.86(9H，S，C(CH
3)
3)，0.97(3H，S，18-CH
3)，1.44(3H，S，19-CH
3)，2.17(3H，S，-OCOCH
3)，4.48(1H，br.S，11β-H)，4.76，4.96(2H，dd，J＝18Hz，21-H
2)，4.94(1H，d，16β-H)，6.01(1H，S，4-H)，6.27(1H，dd，J?10.2，1.2Hz，2-H)，7.27(1H，d，J?9.9Hz，1-H)。
Embodiment 2 16 α-(tertiary butyl dimethyl Si base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-
Diene-3,20-diketone synthetic
With embodiment 1 gained crude product 16 α-(tertiary butyl dimethyl Si base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone-21-acetic ester 1g (1.88mM) is dissolved in the 0.5NKOH/CH of 10ml
3Among the OH, hydrolysis 0.5h under room temperature, TLC show and react completely.Ice-water bath is cooled to 5 ℃, drips among the about 1.5ml of 10%HCl and PH=7, drips to add water to solid and separate out fully again, must 16 α-(tertiary butyl dimethyl Si base)-11 β, and 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone 0.82g, yield: 89%.m.p.：＞120℃。Also carry out recrystallization with column chromatography purification, all can not analyse crystallization, can be directly used in the next step with various solvents.IR(KBr，cm-1)：3447(υOH)，1715(υc＝o)，1659(υc＝o)，1617(υc=c)。
1H-NMR(300MHz，CDCl
3)：δ，ppm，0.01，0.08(2×3H，S，Si(CH
3)
2)，0.86(9H，S，C(CH
3)
3)，0.99(3H，S，18-CH
3)，1.45(3H，S，19-CH
3)，4.49(1H，br.S，11β-H)，4.59，4.26(2H，dd，J＝20.4Hz，21-H
2)，4.98(1H，m，16β-H)，6.03(1H，S，4-H)，6.29(1H，dd，J＝9.9，1.8Hz，2-H)，7.25(1H，d，J＝10.2Hz，1-H)。
Embodiment 3 16 α-(tertiary butyl dimethyl Si base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,
4-diene-3,20-diketone-21-isobutyrate synthetic
With embodiment 2 gained 16 α-(tertiary butyl dimethyl Si base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone 0.5g (1.02mM) is dissolved under the room temperature in the 2.5ml acetone, stirs to add down and grinds and the dry anhydrous K of crossing
2CO
30.28g (2.04mM) and 0.25ml (1.52mM) isobutyric anhydride, stir down backflow 3h until TLC show react completely after, be cooled to 0 ℃, and under ice bath, slowly splash into 50ml water, to no longer separating out precipitation, filter, white powder solid 0.54g, yield 94.5%.Get part with acetone/sherwood oil recrystallization, 16 α-(tertiary butyl dimethyl Si base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone-21-isobutyrate crystallization, m.p.144.5～146.5 ℃.Ultimate analysis: C
31H
48O
7Si, calculated value: C 66.43%, H 8.57%; Measured value: C 66.46%, H 8.72%.IR(KBr，cm-1)：3429(υOH)，1760，1733(υc＝o)，1665(υc＝o)，1620(υc＝c)，1190-1130(υc-o-c)。
1H-NMR(300MHz，CDCl
3)：δ，ppm，0.01，0.06(2×3H，S，Si(CH
3)
2)，0.86(9H，S，C(CH
3)
3)，0.97(3H，S，18-CH
3)，1.45(3H，S，19-CH
3)，1.26，1.21(2×3H，d，21-C(CH
3)
2)，4.48(1H，br.S，11β-H)，4.73，4.97(2H，dd，J＝18Hz，21-H
2)，4.92(1H，d，16β-H)，6.0(1H，S，4-H)，6.28(1H，dd，J＝10.2，1.8Hz，2-H)，7.27(1H，d，J＝9.9Hz，1-H)。
Embodiment 4 11 β, 16 α, 17 α, 21-tetrahydroxy-pregnant steroid-1,4-diene-3,20-diketone-21-is different
Synthesizing of butyric ester
To implement 3 gained, 16 α-(tertiary butyl dimethyl Si base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone-21-isobutyrate 1g (1.78mM) is dissolved under the room temperature in the 10ml methyl alcohol, and ice bath is cooled to 0 ℃, stir and slowly to drip the about 5ml of the 2N HCl aqueous solution down until pH=2-3, stir about 2 hours shows that until TLC the hydrolysis of silicon ether is complete under the room temperature.Use 10%NaHCO
3/ H
2O is about, and 10ml is neutralized to PH=7, adds water to no longer to separate out precipitation, filter, white powder solid 0.75g, yield 93.8%, m.p.＞135 ℃.Get part, with acetone/sherwood oil recrystallization, pure product (II), m.p.220～221 ℃.Ultimate analysis: C
25H
34O
7, calculated value: C 67.26%, H 7.62%; Measured value: C 67.18%, H 7.56%.IR(KBr，cm-1)：3408(υOH)，1730，1717(υc＝o)，1654(υc＝o)，1620(υc＝c)，1157(υc-o-c)。
1H-NMR(300MHz，CDCl
3)：δ，ppm，0.99(3H，S，18-CH
3)，1.45(3H，S，19-CH
3)，1.25，1.21(2×3H，d，21-C(CH
3)
2)，4.48(1H，br.S，11β-H)，4.87，4.96(2H，dd，J＝17.4Hz，21-H
2)，5.0(1H，m，16β-H)，6.02(1H，S，4-H)，6.27(1H，dd，J＝9.9，2.1Hz，2-H)，7.27(1H，d，J＝5.1Hz，1-H)。
Embodiment 5 11 β, 16 α, 17 α, 21-tetrahydroxy-pregnant steroid-1,4-diene-3,20-diketone-21-isobutyl
Synthesizing of acid esters
With embodiment 2 gained 16 α-(tertiary butyl dimethyl Si base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone 9.8g (20mM) is dissolved under the room temperature in the 50ml acetone, stirs to add the anhydrous K of grinding super-dry down
2CO
35.5g (40mM), 5ml (30mM) isobutyric anhydride stirs backflow 3h to TLC to show and reacts completely, and is cooled to 0 ℃, slowly drips the about 35ml to PH=2-3 of 2N HCl, and stirring at room 2h shows that until TLC the hydrolysis of silicon ether is complete, adds 10%NaHCO again
3The aqueous solution is neutralized to PH=7, adds 100-200ml water and does not separate out until there being precipitation, filters, and gets the about 7.64g of white solid, yield 85.7%.mp＞130℃。Get part with acetone/sherwood oil recrystallization, get white crystalline powder, m.p.:219.5-221 ℃.
Synthesizing of embodiment 6 formulas (I) compound
With embodiment 4 or 5 gained, 11 β, 16 α, 17 α, 21-tetrahydroxy-pregnant steroid-1,4-diene-3,20-diketone-21-isobutyrate 9g (20mM), 70%HF 100ml drops in the Plastic Bottle, and cryosel is bathed and is cooled to about-5 ℃, slowly drips 3.5ml (28.97mM) hexahydrobenzaldehyde, drip and finish, keep-5 ℃ to stir 1 hour.TLC shows and uses 10%NH after reacting completely
4OH/H
2The about 1000ml of O neutralization is diluted to PH=7, filter, drying, white powder solid 9.72g, yield 89.2%, m.p.＞130 ℃, HPLC shows R/S=88/12.
Synthesizing of embodiment 7 formulas (I) compound
16 α-(tertiary butyl dimethyl Si base)-11 β with embodiment 3 gained, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone-21-isobutyrate 5g (8.9mM), 70%HF 50ml drop in the Plastic Bottle, cryosel is bathed and is cooled to about-5 ℃, slowly drip 1.51ml (12.5mM) hexahydrobenzaldehyde, drip and finish, keep-5 ℃ to stir 1 hour.TLC shows and uses 10%NH after reacting completely
4OH/H
2The about 500ml of O neutralization is diluted to pH=7, filter, drying, white powder solid 4.05g, yield 84%, m.p.＞120 ℃, HPLC shows R/S=70/30.
Synthesizing of embodiment 8 formulas (I) compound
16 α-(tertiary butyl dimethyl Si base)-11 β with embodiment 3 gained, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone-21-isobutyrate 5g (8.9mM), 70%HF 50ml drops in the Plastic Bottle, cryosel is bathed and is cooled to about-5 ℃, stirs hydrolysis 10～20 minutes earlier, slowly drips 1.51ml (12.5mM) hexahydrobenzaldehyde again, drip and finish, keep-5 ℃ to stir 1 hour.TLC shows and uses 10%NH after reacting completely
4OH/H
2The about 500ml of O neutralization is diluted to pH=7, filter, drying, white powder solid 4.32g, yield 89.7%, m.p.＞135 ℃, HPLC shows R/S=86/14.
Embodiment 9 16 α-(2 '-THP trtrahydropyranyl oxygen base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-
Diene-3,20-diketone-21-acetic ester synthetic
With 1g (2.4mM) 11 β, 16 α, 17 α, 21-tetrahydroxy-pregnant steroid-1,4-diene-3,20-diketone-21-acetic ester is dissolved in 20mlCH
2Cl
2In, stir the dihydropyrane that adds 1.5ml (16.4mM) down, add PTSH
2O 6mg (0.032mM), 20 ℃ are stirred 1.5h down, show until TLC to react completely.Add 10%NaHCO
3Solution is until PH=7.Use ethyl acetate extraction, merge organic layer, use Na
2SO
4Drying concentrates, and with ether/sherwood oil recrystallization, the crystallization after-filtration promptly gets 16 α-(2 '-THP trtrahydropyranyl oxygen base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3, the little yellow crystal 1.03g of 20-diketone-21-acetic ester, yield 85.7%.Get part acetone/sherwood oil recrystallization, mp246.5～218 ℃ ultimate analysis: C
28H
38O
8, calculated value: C 66.93%, H 7.57%; Measured value: C 66.97%, H 7.51%.IR(KBr，cm-1)：3458(υOH)，1755，1730(υc＝o)，1657(υc＝o)，1614(υc＝c)，1170-1145(υc-o-c)。
1H-NMR(300MHz，CDCl
3)：δ，ppm，0.98(3H，S，18-CH
3)，1.44(3H，S，19-CH
3)，2.15(3H，S，-OCOCH
3)，4.68(1H，br.S，11β-H)，3.81，3.55(2H，d，26-H)，4.83，4.96(2H，dd，J＝17.4Hz，21-H
2)，4.82(1H，d，16β-H)，4.20(1H，d，22-H)，6.0(1H，S，4-H)，6.27(1H，dd，J?8.4，1.8Hz，2-H)，7.02(1H，d，J10.2Hz，1-H)。
Embodiment 10 16 α-(2 '-THP trtrahydropyranyl oxygen base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,
4-diene-3,20-diketone synthetic
With embodiment 9 gained crude products 16 α-(2 '-THP trtrahydropyranyl oxygen base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone-21-acetic ester 1g (2.0mM) is dissolved in the 0.2NKOH/CH of 10ml
3Among the OH, hydrolysis 20min under room temperature, TLC show and react completely.Ice-water bath is cooled to 5 ℃, drips among the about 1.5ml of 10%HAC and PH=7～8, drips to add water to solid and separate out fully again, get 16 α-(2 '-THP trtrahydropyranyl oxygen base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone 0.88g, yield: 96.3%.With acetone/sherwood oil recrystallization, crystallization after-filtration, promptly get 16 α-(2 '-THP trtrahydropyranyl oxygen base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3, the little yellow crystal of 20-diketone, mp189.5～191 ℃.Ultimate analysis: C
26H
36O
7, calculated value: C 67.83%, H 7.83%; Measured value: C 67.89%, H 7.81%.IR(KBr，cm-1)：3430(υOH)，1758，1730(υc＝o)，1658(υc＝o)，1614(υc＝c)，1170-1149(υc-o-c)。
1H-NMR(300MHz，CDCl
3)：δ，ppm，0.96(3H，S，18-CH
3)，1.42(3H，S，19-CH
3)，4.45(1H，br.S，11β-H)，3.70，3.90(2H，d，26-H)，4.11，4.63(2H，dd，J＝19.8Hz，21-H
2)，4.84(1H，d，16β-H)，4.18(1H，d，22-H)，6.01(1H，S，4-H)，6.26(1H，dd，J?9.3，2.1Hz，2-H)，7.01(1H，d，J9.9Hz，1-H)。
Embodiment 11 16 α-(2 '-THP trtrahydropyranyl oxygen base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,
4-diene-3,20-diketone-21-isobutyrate synthetic
With embodiment 10 gained 16 α-(2 '-THP trtrahydropyranyl oxygen base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone 1.0g (2.2mM) is dissolved under the room temperature in the 5ml acetone, stirs to add down and grinds and the dry anhydrous K of crossing
2CO
30.6g (4.4mM) and 0.54ml (3.3mM) isobutyric anhydride, stir down backflow 3h until TLC show react completely after, be cooled to 0 ℃, and under ice bath, slowly splash into 50ml water, to no longer separating out precipitation, filter, white powder solid 1.07g, yield 93.2%.Get part with acetone/sherwood oil recrystallization, the crystallization after-filtration promptly gets 16 α-(2 '-THP trtrahydropyranyl oxygen base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone-21-isobutyrate crystallization, mp153.5～156 ℃.Ultimate analysis: C
30H
42O
8, calculated value: C 67.92%, H7.92%; Measured value: C 67.90%, H 7.96%.IR(KBr，cm-1)：3431(υOH)，1765，1740(υc＝o)，1672(υc＝o)，1615(υc＝c)，1170-1149(υc-o-c)。
1H-NMR(300MHz，CDCl
3)：δ，ppm，0.99(3H，S，18-CH
3)，1.44(3H，S，19-CH
3)，1.25，1.21(2×3H，d，21-C(CH
3)
2)，4.45(1H，br.S，11β-H)，3.53，4.0(2H，d，26-H)，4.82，4.94(2H，dd，J＝17.7Hz，21-H
2)，4.81(1H，d，16β-H)，4.19(1H，d，22-H)，6.0(1H，S，4-H)，6.26(1H，dd，J?10.2，1.8Hz，2-H)，7.02(1H，d，J9.9Hz，1-H)。
Embodiment 12 11 β, 16 α, 17 α, 21-tetrahydroxy-pregnant steroid-1,4-diene-3,20-diketone-21-
Synthesizing of isobutyrate
To implement 11 gained, 16 α-(2 '-THP trtrahydropyranyl oxygen base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone-21-isobutyrate 1g (1.9mM) is dissolved under the room temperature in the 10ml methyl alcohol, and ice bath is cooled to 0 ℃, stir and slowly to drip the about 5ml of the 2N HCl aqueous solution down until pH=2-3, stir about 2 hours shows that until TLC the THP trtrahydropyranyl hydrolysis is complete under the room temperature.Use 10%NaHCO
3/ H
2O is about, and 10ml is neutralized to PH=7, adds water to no longer to separate out precipitation, filters, and gets white powder solid 0.78g, yield 92.7%.Get part, with acetone/sherwood oil recrystallization, pure product (II), m.p.220.5～221.3 ℃.
Embodiment 13 11 β, 16 α, 17 α, 21-tetrahydroxy-pregnant steroid-1,4-diene-3,20-diketone-21-is different
Synthesizing of butyric ester
With embodiment 10 gained 16 α-(2 '-THP trtrahydropyranyl oxygen base)-11 β, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone 1g (2.2mM) is dissolved under the room temperature in the 2.5ml acetone, stirs to add down and grinds and the dry anhydrous K of crossing
2CO
30.6g (4.4mM) and 0.54ml (3.3mM) isobutyric anhydride, stir down backflow 3h to TLC and show and react completely, be cooled to 0 ℃, slowly drip the about 5.5ml to PH=2-3 of 2N HCl, stirring at room 2h shows that until TLC the THP trtrahydropyranyl hydrolysis is complete, adds 10%NaHCO again
3The aqueous solution is neutralized to PH=7, and thin up is not separated out until there being precipitation, filters, and gets the about 0.82g of white solid, yield 84.6%.mp＞130℃。Get part with acetone/sherwood oil recrystallization, get white crystalline powder, m.p.:219-220.5 ℃.
Formula (I) compound
Synthesizing of embodiment 14 formulas (I) compound
16 α-(2 '-THP trtrahydropyranyl oxygen base)-11 β with embodiment 11 gained, 17 α, 21-trihydroxy--pregnant steroid-1,4-diene-3,20-diketone-21-isobutyrate 5g (9.4mM), 70%HF 50ml drops in the Plastic Bottle, cryosel is bathed and is cooled to about-5 ℃, and first hydrolysis 15～20min slowly drips 2.4ml (19.9mM) hexahydrobenzaldehyde again, drip and finish, keep-5 ℃ to stir 3 hours.TLC shows and uses 10%NH after reacting completely
4OH/H
2The about 500ml of O neutralization is diluted to pH=7, filter, drying, white powder solid 4.15g, yield 81.5%, m.p.＞130 ℃, HPLC shows R/S=85/15.
Synthesizing of embodiment 15-17 formula (I) compound
Method according to synthesis type (I) compound of embodiment 6,7 and 8, with the nitropropane is solvent, 70% perchloric acid is catalyst-type (I) compound, and the yield of formula (I) compound that 70% perchloric acid obtains during for 4.8ml is respectively 70% (R/S=80/20), 50% (R/S=55/45), 64% (R/S=68/32).
Embodiment 19 formulas (I) compound crude product recrystallization
With embodiment 6 gained formula (I) compound crude product 10g (18.5mM, R/S=88/12) be dissolved in the 28ml acetone, add the 6ml pure water under the stirring and refluxing, leave standstill the nature cooling, crystallization and filtration to be separated out, 75% acetone washing, drying gets white crystals 7.2g, yield 72%, R/S=95/5, m.p.204-206 ℃.
Embodiment 20 formulas (I) compound is refining
Embodiment 19 gained formula (I) compound 5g (9.2mM) are dissolved in the 20ml dehydrated alcohol, add the 8.5ml pure water under the stirring and refluxing, leave standstill cooling, crystallization and filtration to be separated out is with the washing of 50% ethanol/water, drying, get white crystal 3.5g, yield 70%, R/S=98.5/1.5, m.p.207-208.5 ℃.
The condition of HPLC:
Equipment: HP 1084B liquid chromatograph, HP 79850 BLC terminals and UV detector
Column material: Hypersil C18,5um, 125 * 4.6mm
Detect wavelength: 242nm
Moving phase: ethanol: water=6: 4
Column temperature: 45 ℃
Flow velocity: about 1.2ml/ branch
Claims (17)
1. method for preparing with following formula (I) compound,
It comprises following general formula (II) compound is reacted with hexahydrobenzaldehyde under the condition that an acidic catalyst exists,
Wherein, R
1Be selected from hydrogen, THP trtrahydropyranyl, or following formula silylation (A):
R wherein
2, R
3And R
4Can be identical or different, be selected from C independently of one another
1～C
7Alkyl, phenyl.
2. method according to claim 1, its described being reflected in the organic solvent that is selected from halohydrocarbon, nitroparaffins, ether, ketone or ester is carried out.
3. method according to claim 2, its described solvent is 1,4-dioxane, tetrahydrofuran (THF), methylene dichloride, chloroform, acetone, Nitromethane 99Min. or isopropyl ether.
4. method according to claim 1, its described an acidic catalyst is selected from methylsulfonic acid, the tosic acid sulfonic acid at interior one or more, or comprises one or more mineral acid of hydrochloric acid, Hydrogen bromide, perchloric acid, Tetrafluoroboric acid and hydrofluoric acid; If described situation about being reflected at is not with an organic solvent carried out, the consumption of the amount of an acidic catalyst during than with an organic solvent situation of described reaction is many, and this moment, an acidic catalyst also used as solvent.
5. method according to claim 1 is carried out under described being reflected at-30 ℃～60 ℃ of temperature.
6. according to claim 4 or 5 described methods, described an acidic catalyst is a hydrofluoric acid, and temperature of reaction is-20 ℃～40 ℃.
7. method according to claim 6, described temperature of reaction are-15 ℃～10 ℃.
8. method according to claim 1 is as described R
1For THP trtrahydropyranyl or-Si (R
2) (R
3) R
4(A) time, described general formula (II) compound reacts for some time in an acidic catalyst earlier, the reaction times so that the THP trtrahydropyranyl on 16 or-Si (R
2) (R
3) R
4(A) hydrolysis is fallen to be advisable; Adding hexahydrobenzaldehyde again reacts.
9. the midbody compound of general formula below a kind (II),
R wherein
1Be selected from hydrogen, THP trtrahydropyranyl, or the substituting group of following general formula
R wherein
2, R
3And R
4Can be identical or different, be selected from C independently of one another
1～C
7Alkyl, phenyl.
10. midbody compound according to claim 9, described R
2Be selected from methyl, isobutyl-, the tertiary butyl, 1,1,2-trimethylammonium propyl group or phenyl; Described R
3Be selected from methyl, isobutyl-, the tertiary butyl, 1,1,2-trimethylammonium propyl group, phenyl; Described R
4Be selected from methyl, isobutyl-, the tertiary butyl, 1,1,2-trimethylammonium propyl group, phenyl.
11. midbody compound according to claim 10, described R
2Be methyl; R
3Be methyl; R
4Be the tertiary butyl or 1,1,2-trimethylammonium propyl group.
12. according to the described compound of arbitrary claim among the claim 9-11, it is as the application of the intermediate of preparation formula (I) compound.
13. a method for preparing midbody compound as claimed in claim 9, it comprises:
(1) with 11 β, 16 α, 17 α, 21-tetrahydroxy-pregnant steroid-1,4-diene-3,20-diketone-21-acetic ester (being the compound of Formula Il I) is a raw material,
Under acidic conditions, react with dihydropyrane; Perhaps, under alkaline condition, with the reaction of following general formula (B) compound,
R wherein
2, R
3, R
4Can be identical or different, represent the C1-C7 alkyl or phenyl independently of one another; X is a leavings group, and reaction obtains following general formula (IV) compound:
R wherein
1Be THP trtrahydropyranyl, perhaps-Si (R
2) (R
3) R
4(A)
The compound saponification of (2) (1) step gained formulas (IV) obtains the compound of following logical formula V,
Wherein, R
1Be THP trtrahydropyranyl, perhaps-Si (R
2) (R
3) R
4(A)
(3) with (2) step gained formula V compound with isobutyric anhydride or isobutyryl chloride, to its 21-position hydroxyl isobutyl acidylate, promptly get product R
1For THP trtrahydropyranyl or-Si (R
2) (R
3) R
4Substituent general formula (II) compound;
With R
1For THP trtrahydropyranyl or-Si (R
2) (R
3) R
4Substituent general formula (II) compound selective ground its THP trtrahydropyranyl of acidic hydrolysis or-Si (R
2) (R
3) R
4, promptly get R
1General formula (II) compound for hydrogen.
14. method according to claim 13, in wherein said (1) step, described acidic conditions comprises tosic acid, HClO
4Described alkaline condition is provided by the organic bases that comprises triethylamine, DIEA, N-methylmorpholine, piperidines, imidazoles, pyridine and piperazine; Described being reflected at comprises methylene dichloride, and dimethyl formamide, imidazoles and tetrahydrofuran (THF) carry out in interior aprotic organic solvent; R in the described formula (B)
2Be selected from methyl, isobutyl-, the tertiary butyl, 1,1,2-trimethylammonium propyl group, and phenyl; R
3Be selected from methyl, isobutyl-, the tertiary butyl, 1,1,2-trimethylammonium propyl group, and phenyl; R
4Be selected from methyl, isobutyl-, the tertiary butyl, 1,1,2-trimethylammonium propyl group, and phenyl; Described leavings group is selected from chlorine, bromine or iodine.
15. method according to claim 13, in wherein said (2) step, described saponification is in organic alcoholic solution of mineral alkali, at room temperature carry out, here, mineral alkali is selected from sodium hydroxide, potassium hydroxide, and organic alcohol is selected from methyl alcohol, ethanol, propyl alcohol or Virahol.
16. method according to claim 13, in wherein said (3) step, described isopropylformic acid anhydridization is at K
2CO
3Carry out in/the acetone soln.
17. method according to claim 14, R described in wherein said (1) step
2Be methyl; R
3Be methyl; R
4Be the tertiary butyl or 1,1,2-trimethylammonium propyl group, X are chlorine; Described reaction was at room temperature carried out 0.5～10 hour.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007056181A2 (en) * | 2005-11-02 | 2007-05-18 | Sicor, Inc. | Process for the preparation of ciclesonide |
| CN106883283A (en) * | 2015-12-15 | 2017-06-23 | 天津金耀集团有限公司 | Ciclesonide monohydrate and its crystal formation and preparation method |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GR1001529B (en) * | 1990-09-07 | 1994-03-31 | Elmuquimica Farm Sl | Process for the obtainment of a new pregna-1,4-diene-3,20-dione -16-17-acetal-21 esters |
| NZ265054A (en) * | 1993-04-02 | 1997-08-22 | Byk Gulden Lomberg Chem Fab | 16-hydroxy prednisolone cyclohexanecarboxaldehyde acetal derivatives |
| EP0749438B1 (en) * | 1994-03-09 | 2000-12-13 | Byk Gulden Lomberg Chemische Fabrik GmbH | Novel silyl compounds and their use |
| DE19635498A1 (en) * | 1996-09-03 | 1998-03-26 | Byk Gulden Lomberg Chem Fab | Process for epimer enrichment |
| EA006231B1 (en) * | 2000-11-10 | 2005-10-27 | Алтана Фарма Аг | Process for the production of 16,17-[(cyclohexylmethylen)bis(oxy)]-11,21-dihydroxy-pregna-1,4-dien-3,20-dion or its 21-isobutyrat by transketalisation |
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2004
- 2004-10-29 CN CNB2004100867323A patent/CN100345864C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007056181A2 (en) * | 2005-11-02 | 2007-05-18 | Sicor, Inc. | Process for the preparation of ciclesonide |
| WO2007056181A3 (en) * | 2005-11-02 | 2007-08-02 | Sicor Inc | Process for the preparation of ciclesonide |
| CN106883283A (en) * | 2015-12-15 | 2017-06-23 | 天津金耀集团有限公司 | Ciclesonide monohydrate and its crystal formation and preparation method |
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